This is a re-revised application for a Mid-Career Investigator Award in Patient-Oriented Research (K24). The candidate, Mark W. Bondi, Ph.D., ABPP/CN, Associate Professor of Psychiatry at the University of California San Diego, proposes to pursue a program of research and mentoring activity on the structural and functional neuroimaging changes related to older persons at risk for Alzheimer's disease (AD). The research plan includes two projects for which the candidate is PI, and one as Co-lnvestigator, all of which have been funded and are ongoing, and new research proposed (see Appendix B). The candidate's career goals are (1) to advance his progress in becoming a leader in the scientific study of neuroimaging changes related to those at risk for AD as well as those with preclinical or early clinical AD;(2) to increase his expertise in both established and emerging neuroimaging techniques for translational efforts in clinical detection of AD, its accurate differentiation from other disorders to which older adults are prone, and potential treatment response to therapeutic trials;and (3) to continue to mentor junior scientists and expand such mentorship to the aforementioned skill domains. He has made a strong commitment to integrating neuropsychological and neuroimaging investigations of persons at genetic risk for AD. Activities for his continued career development include (1) consultation with leading research neuroimaging scientists;(2) didactic and experiential training in emerging functional neuroimaging techniques (e.g., arterial spin labeling, diffusion tensor imaging);(3) participation in departmental and campus-wide neuroimaging seminars and meetings;and (4) expanding his capabilities as a research mentor. Funding of this Mid-Career Investigator Award will provide him with the opportunity to substantially increase the time devoted to clinical research activities, thus enhancing his continued development as a clinical investigator and as a mentor to junior clinician investigators interested in the integration of neuropsychology and neuroimaging. Since little is known concerning the underlying functional brain changes in at-risk groups on susceptible cognitive functions prior to AD onset, this application promises to contribute important new methodologies in the characterization of neurobiological substrates surrounding the development of Alzheimer's disease. If successful, our ability to preclinically detect and monitor Alzheimer's disease will have far-reaching implications for early treatment.